The invention relates to a simple and industrially readily executable method of producing thiazolidine base and salts thereof.
Thiazolidine can serve as an intermediate for the synthesis of aminoacyl and peptidyl thiazolidides, which have both a diagnostic and a therapeutic value as enzyme inhibitors [H.-U. DEMUTH, J. Enzyme Inhibition 3, 249 (1990)].
Since aminoacyl thiozolidides are suitable, inter alia, for the regulation of the blood sugar level in mammals, the preparation of these compounds and their parent materials using a cost-effective, commercially applicable process is of medical, pharmaceutical and economical interest [cf DE 19,616,486].
It is known that thiazolidine and thiazolidine derivatives can be obtained by refluxing aldehydes with aminoethyl sulfate or aminoethyl halides and sodium sulfide in aqueous solution under excess energy input over a period of several hours. The yields are ca 60% of theory [cf U.S. Pat. No. 4,584,407].
It is an object of the present invention, however, to provide a process for the production of thiazolidine base or the salts thereof in which no excess energy input is necessary.
The present invention now provides a process for the production of thiazolidine base and salts thereof which is characterized in that hexamethylenetetramine of formula (I) as shown in FIG. 1 is caused to react with cyst amine or salts thereof of formula (II) as shown in FIG. 2. in which X(xe2x88x92) denotes an acid residue, X(xe2x88x92) being preferably a halide or sulfate.
It is extremely surprising to find that this process gives the free base thiazolidine and salts thereof in high yields of very pure substance without it being necessary to apply excess quantities of heat during the reaction. This constitutes a cost-effective and technological advantage of the process of the invention particularly as regards the industrial production of thiazolidine [cf EP 0,054,409].
In the present invention, the reaction can take place, eg, in a polar solvent such as an alcohol. Preferred solvents are methanol and/or ethanol.
Another economical and technological advantage of the process of the invention for the industrial production of thiazolidine is the fact that hexamethylenetetramine is acceptable as regards the pharmaceutical use of the secondary products of thiazotidine, since it is pharmaceutically acceptable: for many years it has been used as a urine disinfectant and for food preservation [cf Mutschler, Arzneimittelwirkungen, pp. 572 et seq., Stuttgart: Wissenschaftliche Verlagsgs. (1986)].
Preferably, ammonia is used as the initial batch and/or is added during the reaction. By this means, synthesis can be carried to the stage of the free base in a single step [cf S. Ratner, H. T. Clarke, J. Am. Chem. Soc. 59, pp 200-206 (1937)] so that additional complicated and expensive reaction stages can be omitted.
The process of the invention, which is designed for both laboratory-scale and commercial-scale applications, is carried out, for example, by adding hexamethylenetetramine to a preferably methanolic solution of a cysteamine salt all at once or in a number of portions, as solid matter or dissolved in a solvent. The mixture can be stirred for several hours at room temperature, or it may be stirred at temperatures around 30-35xc2x0 C. The stated dosing procedure can take place in reverse order if desired.
The process of the invention must not necessarily be carried out under a blanket of inert gas as in other processes [cf EP 0,695,744].
The thiazolidine produced by the process of the invention can be used as starting material for the production of pharmaceutically useful active substances. The invention is illustrated with reference to the following example.